ClinicSpeak: explaining the theory behind progressive MS

A new infographic to explain progressive MS. #ClinicSpeak #MSBlog #MSResearch

"Some readers  have taken to asking me questions by email; I would prefer it if you asked via the comments box. You may have noticed I am very poor at responding to emails; I get too many. However, I will give this one a go. This post is in response to the following question."

"Ocrelizumab in relapsing MS results; very good efficacy with a very favourable safety profile. Ocrelizumab will allow us to flip the pyramid and use highly effective treatments very early in the disease in the majority of MSers. However, my initial enthusiasm for ocrelizumab has been dampened by Steve Hauser's comments that a large number of their patients with relapsing MS who have been treated for 10+ years on rituximab have now developed SPMS. If this is correct then anti-CD20 B-cell depletion will not be a panacea.

Question: Can you elaborate a bit more about this issue in your blog, it would be most appreciated by your readers, including me?

"People with MS and those of us who treat the disease want a cure. However, we may have a cure in hand and yet we don't reverse or prevent progressive disease. How can this be? I have tried to capture all the issues in this infographic; it is a work in progress so if you don't understand it please let me know and I will adapt it."

"Focal inflammation damages nerves in two ways. It can shred and destroy nerve fibres as part of the initial inflammatory stage (acute neurodegeneration) or it can damage nerves and leave them functioning, but the resulting damage primes them to die off in the future; so called delayed neurodegeneration. The mechanisms that result in delayed neurodegeneration of nerves are many and include innate immunity (hot microglia), energy deficits (mitochondrial dysfunction), excitotoxicity (calcium overload), free radicals, premature ageing, etc. Clearly anti-inflammatory drugs that prevent new lesions formation, such as ocrelizumab, will not be able to prevent the delayed neurodegeneration from previous inflammatory lesions. What has happened in the past has happened; i.e. the water under the bridge analogy. So if you have relapsing MS and have had a lot of inflammatory activity in the past that has damaged many nerve fibres, even if you go onto a highly effective DMT such as ocrelizumab, that renders you NEDA, it is not going to prevent the ongoing loss of nerve fibres that are primed to die off from previous inflammation in the future."

"What protects you from entering the clinically-apparent secondary progressive phase of the disease is reserve capacity, i.e. the surviving healthy nerve fibres in nerve pathways keep you functioning normally. I therefore suspect that those patients of Steve Hauser, who have been treated with rituximab and have now become secondary progressive, had a low reserve capacity and a large number of damage nerve fibres that had been primed to die off in the future. In other words they were treated with rituximab too late to prevent SPMS."

"Please note that Steve Hauser's observations, and the above theoretical explanation, are not new and have been noted with with other high efficacy DMTs, i.e. mitoxantrone, HSCT, natalizumab and alemtuzumab. There are two conclusions to be drawn from the above observations and theory; (1) it is best to have your MS treated effectively early in the disease course to maximise your reserve capacity, or (2) we need additional add-on neuroprotective therapies to target the delayed neurodegenerative processes referred to above. The latter includes avoiding or reversing factors that prematurely age the nervous system. The latter is what underpins our Brain Health campaign."

"So unless you get treated with ocrelizumab, or another high efficacy DMT, early in the course of your disease it may not prevent you entering the progressive phase of the disease, i.e. it will not be a panacea."

"There is one caveat to the last paragraph. There is an alternative hypothesis that the progressive phase of MS is driven by antibodies produced within the central nervous system. Although ocrelizumab targets B cells it doesn't target long-lived plasma cells within the brain and spinal cord of MSers. None of the current crop of DMTs has been convincingly shown to target the so called intrathecal plasma cells. In fact plasma cells are very difficult to target biologically, particularly within the CNS. Please watch this space; I suspect there is going to be a flurry of activity around plasma cell targeting as a potential treatment for MS. I did mention in my talk at ECTRIMS that there are some reports that MSers on long-term natalizumab seem to lose  their OCBs (oligoclonal bands or antibody bands); it now emerges that plasma cells live in a 'niche' or home and that to keep them in the niche they use the VCAM-1-VLA-4 adhesion molecule interaction. Natalizumab disrupts this interaction and hence it is plausible that natalizumab may reduce the life expectancy of intrathecal (inside the CNS) plasma cells. If this is the case natalizumab may have the edge on the other DMTs in this regard. However, the data on natalizumab and OCBs needs confirming and to be studied in more detail. Already a German consortium of investigators' have not confirmed the earlier reports."

"Finally, those of you interested in animal models will find the two studies below of interest. They try and model the early and late effects of inflammation in driving neurodegeneration. In other words there is animal data to support the delayed neurodegeneration theory; it is not simply a thumb suck."

Animal model 1: Mindur et al. Early treatment with anti-VLA-4 mAb can prevent the infiltration and/or development of pathogenic CD11b+CD4+ T cells in the CNS during progressive EAE. PLoS One. 2014 Jun 4;9(6):e99068. doi: 10.1371/journal.pone.0099068.

Background: Natalizumab is a humanized monoclonal antibody against the leukocyte adhesion molecule very late antigen (VLA)-4, and is currently an approved therapy for patients with relapsing-remitting multiple sclerosis (RRMS). However, it is unknown whether natalizumab is beneficial for progressive forms of MS.

Objectives & Methods: Therefore, we assessed the effects of anti-VLA-4 monoclonal antibody (mAb) therapy in a progressive experimental autoimmune encephalomyelitis (EAE) mouse model. 

Results: Notably, we found that early therapy could significantly reduce the severity of progressive EAE, while treatment initiated at an advanced stage was less efficient. Furthermore, we observed the accumulation of a novel subset of GM-CSF-producing CD11b+CD4+ T cells in the CNS throughout disease progression. Importantly, early therapeutic anti-VLA-4 mAb treatment suppressed the accumulation of these GM-CSF-producing CD11b+CD4+ T cells in the CNS along with activated microglia/macrophages populations, and also conferred a protective effect against inflammation-mediated neurodegeneration, including demyelination and axonal loss. 

Conclusion: Collectively, our data suggest that early treatment with anti-VLA-4 mAb can provide neuroprotection against progressive CNS autoimmune disease by preventing the accumulation of pathogenic GM-CSF-producing CD11b+CD4+ T cells in the CNS.

Animal model 2: Hampton et al. Neurodegeneration progresses despite complete elimination of clinical relapses in a mouse model of multiple sclerosis. Acta Neuropathol Commun. 2013 Dec 23;1:84. doi: 10.1186/2051-5960-1-84.

BACKGOUND: Multiple Sclerosis has two clinical phases reflecting distinct but inter-related pathological processes: focal inflammation drives the relapse-remitting stage and neurodegeneration represents the principal substrate of secondary progression. In contrast to the increasing number of effective anti-inflammatory disease modifying treatments for relapse-remitting disease, the absence of therapies for progressive disease represents a major unmet clinical need. This raises the unanswered question of whether elimination of clinical relapses will prevent subsequent progression and if so how early in the disease course should treatment be initiated. Experimental autoimmune encephalomyelitis in the Biozzi ABH mouse recapitulates the clinical and pathological features of multiple sclerosis including relapse-remitting episodes with inflammatory mediated demyelination and progressive disability with neurodegeneration.

OBJECTIVES: To address the relationship between inflammation and neurodegeneration we used an auto-immune tolerance strategy to eliminate clinical relapses in EAE in a manner analogous to the clinical effect of disease modifying treatments.

RESULTS: By arresting clinical relapses in EAE at two distinct stages, early and late disease, we demonstrate that halting immune driven demyelination even after the first major clinical event is insufficient to prevent long-term neurodegeneration and associated gliosis. Nonetheless, early intervention is partially neuroprotective, whereas later interventions are not. Furthermore early tolerisation is also associated with increased remyelination.

CONCLUSIONS: These findings are consistent with both a partial uncoupling of inflammation and neurodegeneration and that the regenerative response of remyelination is negatively correlated with inflammation. These findings strongly support the need for early combinatorial treatment of immunomodulatory therapies and neuroprotective treatments to prevent long-term neurodegeneration in multiple sclerosis.

CoI: multiple

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